biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2025-580biopreparat-580Research ArticleТЕМА НОМЕРА: ТРЕНДЫ КОНТРОЛЯ КАЧЕСТВА И СТАНДАРТИЗАЦИИ БИОЛОГИЧЕСКИХ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВISSUE TOPIC: TRENDS IN QUALITY CONTROL AND STANDARDISATION OF BIOLOGICALSРеализация концепции Quality by Design для генотерапевтического лекарственного препарата на основе аденоассоциированного вирусного вектораImplementation of the quality-by-design concept for an adeno-associated viral vector-based gene therapyhttps://orcid.org/0000-0003-1176-5829КопеинД. С.KopeinD. S.

Копеин Дамир Сергеевич, канд. биол. наук

ул. Тестовская, д. 10, Москва, 123112

Damir S. Kopein, Cand. Sci. (Biol.)

10 Testovskaya St., Moscow 123112

kopein@generium.ruhttps://orcid.org/0000-0003-3754-9198ПорошинГ. Н.PoroshinG. N.

Порошин Григорий Николаевич

ул. Тестовская, д. 10, Москва, 123112

Grigory N. Poroshin

10 Testovskaya St., Moscow 123112

g.poroshin@generium.ruhttps://orcid.org/0000-0002-1314-894XХамитовР. A.KhamitovR. A.

Хамитов Равиль Aвгатович, д-р мед. наук, проф.

ул. Тестовская, д. 10, Москва, 123112

Ravil A. Khamitov, Dr. Sci. (Med.), Prof.

10 Testovskaya St., Moscow 123112

khamitov@ibcgenerium.ruАкционерное общество «ГЕНЕРИУМ»РоссияGENERIUM JSCRussian Federation202525062025252141155Copyright © Копеин Д.С., Порошин Г.Н., Хамитов Р.A., 20252025Копеин Д.С., Порошин Г.Н., Хамитов Р.A.Kopein D.S., Poroshin G.N., Khamitov R.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/580ВВЕДЕНИЕ

ВВЕДЕНИЕ. Производители генотерапевтических лекарственных препаратов на основе аденоассоциированных вирусов (ААВ) сталкиваются в настоящее время с рядом системных проблем, в основе которых лежат трудности в оценке качества препаратов из-за недостаточной базы научных данных, опыта и несовершенства нормативных и регуляторных требований. Риск-ориентированный подход для оценки критических показателей качества в рамках концепции «качество через дизайн» (Quality by Design, QbD) обеспечивает повышение эффективности разработки и производства высокотехнологичных лекарственных препаратов.

ЦЕЛЬ

ЦЕЛЬ. Определение критических показателей качества и их диапазонов при разработке генотерапевтических лекарственных препаратов на основе ААВ для лечения миодистрофии Дюшенна в рамках реализации концепции «качество через дизайн» (QbD).

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Проведен анализ подходов к разработке технологии производства ААВ с использованием концепции QbD. Обоснован перечень основных характеристик ААВ и доступных данных об их влиянии на пациентов с точки зрения эффективности и безопасности, в том числе иммунного ответа на лечение. Проведена оценка рисков и определен перечень критических показателей качества ААВ. В ходе разработки процесса производства ААВ определены диапазоны значений для показателей качества ААВ вектора: вирусный и инфекционный титры, наличие репликативно-компетентных AАВ, содержание пустых капсидов и остаточных примесей (белки, плазмидная ДНК и остаточная ДНК продуцента). Проведена комплексная оценка рисков при определении целевого профиля продукта — препарата на основе ААВ для лечения миодистрофии Дюшенна. Разработан перечень критических показателей качества препарата и основные требования к аналитическим методикам, а также установлены диапазоны значений параметров для контроля качества продукта.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Применение концепции QbD и риск-ориентированного подхода является важным этапом в идентификации критических показателей качества при разработке генотерапевтических лекарственных препаратов. Использование методологии QbD позволяет сформировать новые регуляторные стандарты оценки безопасности и эффективности генотерапевтических препаратов, а также осуществлять их фармацевтическую разработку и промышленное производство.

INTRODUCTION

INTRODUCTION. Currently, manufacturers of adeno-associated virus (AAV)-based gene therapy products are facing a number of systemic problems stemming from the difficulties in assessing the quality of medicinal products due to insufficient scientific data, limited experience, and imperfect regulatory requirements. However, a risk-based approach to assessing critical quality attributes (CQAs) within the the framework of Quality by Design (QbD) can ensure improved efficiency in the development and production of advanced therapy medicinal products.

AIM

AIM. This study aimed to identify QbD-based CQAs and associated specifications for the development of AAV-based gene therapy products for Duchenne muscular dystrophy.

DISCUSSION

DISCUSSION. This study involved an analysis of QbD-based approaches to the development of AAV production technologies. The authors substantiated a list of the main AAV characteristics and collated available data on their impact on patients in terms of the efficacy and safety of gene therapy products and, in particular, the immune response to treatment. Following a risk assessment, the authors identified a list of CQAs for AAVs. When developing an AAV production process, the authors determined specifications for AAV CQAs, including viral and infectious titres, the presence of replication-competent AAVs, the percentage of empty capsids, and residual impurities (proteins, plasmid DNA, and residual host-cell DNA). A comprehensive risk assessment was conducted to determine the quality target product profile for an AAV-based gene therapy product for Duchenne muscular dystrophy. The authors listed the CQAs, developed the basic requirements for the applicable analytical procedures, and established the CQA specifications for the gene therapy product.

CONCLUSIONS

CONCLUSIONS. The use of QbD principles and risk-based approaches is an important step in CQA identification during the development of gene therapy products. The QbD methodology facilitates drafting new regulatory standards for the evaluation of the safety and efficacy of gene therapy products and helps with the development and commercial-scale manufacturing of such products.

генная терапиягенотерапевтический лекарственный препаратаденоассоциированный вирусААВаденоассоциированный вирусный векторQuality by Designкритические показатели качествацелевой профиль качества препаратариск-ориентированный подходтехнология получения ААВмиодистрофия Дюшеннаgene therapyadvanced therapy medicinal productATMPadeno-associated virusAAVadenoassociated viral vectorQuality by DesignQbDcritical quality attributeCQAquality target product profileQTPPrisk-based approachAAV production technologyDuchenne muscular dystrophyDMDReferencesСолдатов АА, Авдеева ЖИ, Горенков ДВ, Хантимирова ЛМ, Гусева СГ, Меркулов ВА. Проблемные аспекты разработки и регистрации генотерапевтических препаратов. БИОпрепараты. Профилактика, диагностика, лечение. 2022;22(1):6–22. https://doi.org/10.30895/2221-996X-2022-22-1-6-22Soldatov AA, Avdeeva ZhI, Gorenkov DV, Khantimirova LM, Guseva SG, Merkulov VA. Challenges in development and authorisation of gene therapy products. Biological Products. 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The authors declare that there are no conflicts of interest present.